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Executive Summary

Regulators and industry officials agree that despite efforts to spur development of continuous manufacturing, uptake has been slow globally. FDA still is on learning curve and acknowledges a knowledge gap around some of the higher order principles associated with continuous manufacturing.

The pharmaceutical industry and regulatory authorities agree that continuous manufacturing still is in the early stages of adoption, short of a “tipping point.”
But while FDA admits efforts to advance continuous manufacturing are stymied by knowledge gaps, a Pfizer Inc. executive warns regulators need to work together to develop uniform interpretations of continuous manufacturing, and not doing so could impede adoption.

These assertions were made at the 3rd FDA/Product Quality Research Institute conference on Advancing Product Quality, March 22-24 in Rockville, Md. Regulators from the US, the EU and Japan highlighted some of the initiatives underway to promote continuous manufacturing in their regions. They also described how they are relying on extensive collaboration with industry and academia to help educate reviewers and industry on continuous manufacturing.

In the US, two approvals have been made to date for continuous manufacturing. The first was Vertex Pharmaceuticals Inc.’s cystic fibrosis treatment Orkambi in in July 2015 and the second was for Janssen Pharmaceuticals Inc.’s supplemental new drug application to switch its HIV-1 treatment Prezista from batch to continuous manufacturing in April 2016.

Celia Cruz, director of the Office of Testing and Research in FDA’s Center for Drug Evaluation and Research, said to expect some more approvals for continuous manufacturing in the next two to three years. Cruz, who serves on the agency’s Emerging Technology Team (ETT, formed in 2013 to promote the use of new technologies in pharmaceutical manufacturing, said there is a “lot of promise in some of these applications coming through. We will be as busy as you are to try to make sure that this becomes a reality.”

Rapti Madurawe, division director of the Office of Process and Facilities in FDA’s Center for Drug Evaluation and Research said the agency recognized early on that continuous manufacturing needed “significant nurturing” to become a reality, and is conducting an “unprecedented level of external outreach with industry, academia and other regulators.”

Not At Tipping Point

Regulators and several industry members agreed that despite this outreach, uptake has been sluggish.

“I want to look at where we were with continuous manufacturing and I think we are on a journey. In 2017 I think we would place it in a continuum. The science and principles and the feasibility we have seen commercially. Are we there yet? Are we ready to turn the page?" said Diane Zezza, vice-president global regulatory CMC for Novartis AG.

"You might say we’re are at infancy in emerging technology with continuous manufacturing and we still have quite a way to go before we achieve broad acceptance,” Zezza added.

Christine Moore, global head and executive director of CMC policy for Merck & Co. Inc., made a similar observation. “We are now in the cautiously optimistic stage. We have seen some wins related to continuous manufacturing and approvals in certain regions but we are not there yet. I would say that we’re not past the tipping point.”

“I think we are still at the point where one bad regulatory experience could still shift the balance of industry looking to invest in this new technology,” added Moore, formerly acting director of FDA’s Office of New Drug Quality Assessment and an early proponent of continuous manufacturing.

She pointed out acceptance is more common now than two or three years ago, when there was “a lot of pessimism with people saying ‘yeah, right, I understand where you are going but I don’t think this is going to work because it’s not value-added.’”

Still, lot of uncertainty remains about continuous manufacturing on both sides.

The industry has questions related to “will this application be approved, what are the expectations for our products and how many questions am I going to get in my application with the new technologies. And from the review side, what should they expect, how will they get the information they need to do an inspection,” , Moore said.

One common issue and concern from both sides is that continuous manufacturing involves a “lot more work. We are putting new platforms there. Is it worth the extra work and the extra risk?” she said.

FDA’s Madurawe concurred. “We think this is a great benefit for the industry that means that continuous manufacturing is possible and there are no regulatory barriers in implementing continuous manufacturing but we have a way to go. Like Christine said, we are not at the tipping point yet. There are big opportunities to do more.”

FDA On Learning Evolution of Concepts

Cruz said FDA has made great strides already over the past five years in advancing a regulatory framework for continuous manufacturing. Yet, she admitted the agency is working from a limited knowledge base.

“For us to admit that we have limited experience takes some guts, but here it is. This is why we have the commitment to take some time to do this. We consider this a learning experience in FDA, the industry and academia,” Cruz said.

She added FDA has evolved its thinking on continuous manufacturing, with early discussions focused on return on investment and the definition of a batch. “Five years ago how would we define batch? We got a little hung up about that in the beginning. At the end, we moved on to early discussions on sampling frequency and residence time distribution.”

Currently, discussions focus on model maintenance. “We are having a lot of discussions about this. This is now,” Cruz said.

There also are conversations on material attributes, excipients and run time. Not discussed yet are some higher order principles in continuous manufacturing such as advanced process control and harmonization.

Don’t Let Fear Of Questions Stop Adoption

Madurawe said the industry should not be afraid when FDA asks questions on continuous manufacturing applications, and should not interpret questions to mean lack of regulatory support. The agency, after all, still is in the learning mode.

In fact, she said, it’s important for the conversation with FDA about continuous manufacturing applications to begin before they’re submitted. At the conference, she said, there was a question about FDA being prepared for all the applications that are currently in the pipeline.

"We are extremely well prepared and trained to handle that and handle more, but we are not at the point where we are at a plug-and-play stage where companies can just drop their applications without any prior conversations,” Madurawe said,

“Questions facilitate shared learning of new concepts and help reach consensus and lead to first-cycle approval. Do not let fear of questions impede the adoption of continuous manufacturing,” she added.

Noting that knowledge gaps in the industry have yet to be overcome in advancing continuous manufacturing, she said, “The current workforce is trained in batch manufacturing,” not continuous manufacturing.

For example, manufacturers need to train employees in advanced process monitoring and multivariate approaches for assessing process and product quality, and in using predictive models to support real-time release testing.

Additionally, having the statistical skills to handle the huge amount of data emanating from continuous processes also would be useful, an area where academia can help in training and educating the future workforce, she said.

Madurawe also said the industry is underutilizing PAT tools, which could help ensure that processes are in control in real time, a “real asset” in continuous manufacturing.

EMA And Japan: No Roadblocks

Like FDA officials, representatives from the EU and Japan said they are encouraging the pharmaceutical industry to submit applications for continuous manufacturing.

Dolores Herman, a European Medicines Agency quality specialist, said although specific guidance is not available, existing guidance supports this approach.

Herman said these EU guidances address continuous manufacturing:

International Council on Harmonization’s Q8, Q9, Q10 and Q11 guidelines, because the principles they set forth apply to enhanced development;
EU guideline on process validation, which in 2014 introduced the concept of continued process verification;
EU guideline on real-time release testing;
EU guideline on manufacture of drug product, which is currently under revision;
EU guideline on chemistry of new active substances, published in November 2016;
EU guideline on use of near infrared spectroscopy, which was revised in 2014;
European Pharmacopeia (PhEur) chapter on chemometrics;
A quality-by-design question-and-answer guide that resulted from a joint EMA/FDA QbD pilot; and
GMP annexes 15 and 17.
In addition, Herman said multiple regulatory platforms, tools and incentives promote continuous manufacturing. These include scientific advice from EMA’s Committee for Medicinal Products for Human Use, where members offer advice on appropriate tests and studies to support continuous manufacturing; the PAT team, which supports process analytical technology and QbD activities in the EU; the Innovation Task Force, a platform for early scientific dialogue; and the EMA SME office, which offers dedicated support to small and medium pharmaceutical companies.

Those efforts have borne fruit, she said, as the PAT team and pharmaceutical manufacturers have had several discussions and several requests have been made for scientific advice on continuous manufacturing. Two applications have been submitted in the EMA's centralized procedures and one is under the EMA-FDA QbD pilot program.

Herman said while experience is limited to date, EMA recommends early dialogue with regulators during development of continuous manufacturing.

Japan Encourages Continuous Manufacturing

Yoshihiro Matsuda, a senior scientist for quality at Japan’s Pharmaceuticals and Medical Devices Agency, said the agency supports the development of continuous manufacturing and is collaborating with outside working groups to ensure it is adopted. "We are learning about CM technology,” he said.

“PMDA would like to encourage industry to introduce this innovative manufacturing technology,” Matsuda said, adding that adopting continuous manufacturing means “avoiding poor quality, avoiding scale-up issues, and reducing inventory.”

PMDA is collaborating with the Japan Agency for Medical Research and Development to study continuous manufacturing and is providing training to GMP inspectors. PMDA is also collaborating with the Japan Society of Pharmaceutical Machinery and Engineering to provide training to reviewers on PAT and multivariate analysis.

He said PMDA also established the Innovative Manufacturing Technology Working Group (IMTWG) within PMDA in July 2016 to propose a regulatory framework for continuous manufacturing. The working group consists of Matsuda and three others who represent PMDA’s offices of new drugs, regulatory science, and manufacturing quality and compliance.

The IMTWG activity plan is to organize face-to-face meetings with FDA and EMA, visit continuous manufacturing sites and collaborate on a national research project on pharmaceutical quality control. It plans to publish a draft points-to-consider guidance on continuous manufacturing later this spring.

Regulatory Disconnects Hurt CM

Despite encouragement to embrace continuous manufacturing, one pharma industry official questioned whether it is worth the investment if regulators create unnecessary hurdles to register products.

Roger Nosal, vice-president and head of global CMC for Pfizer, said the firm decided not to pursue a continuous manufacturing submission for a well-established high-volume product in 2005 because the global regulatory requirements were cost prohibitive.

“The regulatory hurdles to get this approved would have been immense. We figured it would take seven years to get approved globally and it would cost us twice what it would have saved us,” Nosal said

However, the situation has improved over the past decade, partly due to to improved receptivity from regulators as well as improved quality assurance and flexible manufacturing capacity, he said.

Because of these more favorable business conditions, Pfizer is pursuing portable, continuous, miniature and modular (PCMM) system as a platform for specific products, Nosal said.

PCMMs, flexible mini-factories that can be installed into existing warehouse spaces and used for development and commercial manufacturing, use PAT and advanced process control (APC) for real-time monitoring. (Also see "Industry Proponents Make the Case for Continuous Manufacturing" - Pink Sheet, 29 Apr, 2015.)

“This is a very nice and compact manufacturing suite that can be carried on a semi-trailer and they can be installed and moved around as necessary,” Nosal said.

“Because it is portable, you can do a lot besides direct compression. Our plan is to get this registered pretty soon. We have come a long way. We decided it is much better to do continuous manufacturing now than it was 10 years ago. It was too much of a regulatory burden,” he added.

Pfizer intends to register PCMM for a new product candidate during the next 18 months.

Yet Nosal said Pfizer anticipates similar regulatory challenges it encountered previously since few precedents are set and health authorities have not established definitive regulatory position on certain issues.

For example, there is still some regulatory uncertainty about the definition of a batch, lot traceability, batch uniformity, process upsets, the ability to change batch size, differentiating APC from PAT monitoring, the lifecycle control of raw materials, site transfers, inspections, compendial criteria and the volume of submission data. Each regulator has different definitions of these terms.

“The definition of a batch is still essentially an issue, yet we are much closer to figuring out what that is. Lot traceability is a big deal but it has always been a big deal,” Nosal said.

“What I worry about with continuous manufacturing, because it is new and it is a little bit complicated to understand initially, is that if we don’t start to think about this sooner we will wind up having multiple views of what continuous manufacturing is and we will be establishing different continuous manufacturing criteria.”

Too Much Information

Nosal also noted regulatory challenges that are part of a larger problem of recent global regulatory trends.

These include “unpredictable application of ICH guidelines, increased requests to review GMP information, divergent expectations for starting materials controls and requests for even more stability data, and differing specifications,” he said.

There was some discussion during the meeting that ICH may adopt continuous manufacturing as a work item. Moore said there are plans to add continuous manufacturing as a work item on the ICH agenda, and that a decision will be made on this in June or July.

Nosal pointed out another problem is differing inspection outcomes. He said at one of Pfizer's sites in 2016, four regulatory authorities made a total of 173 inspections.

"They all gave us different observations and in some cases contradicted each other. This doesn’t help. With continuous manufacturing, we are definitely going to need inspections, and we are going to need inspections that are good inspections.”

Nosal said requests for CMC information have grown tremendously over the past 20 years and that much of this information is not relevant. “I should not have to be providing cleaning validation and providing all executed batch records for products.”

“When I started in regulatory in 1994 and I filed a CMC section around the world, this was about 1,000 pages of CMC information for a small molecule. This was about six volumes for a biologic. Now we are filing on the order of about eight or nine volumes for a small molecule and about 26 volumes for a biologic. That is a lot of additional information and data. This is creating a burden for all of us. There has to be a better way.”

“When the rubber hits the road and we actually file a submission, that is when you find out if things are going to work. We have to start encouraging these discussions not just among ourselves, but internally and externally with the regulators so that the regulators are privy to all of the things we are doing.”

CM Fully Integrated By 2030

Other pharmaceutical officials predicted full uptake of continuous manufacturing is inevitable, but will take time to reach full adoption.

Robert Meyer, a chemical engineer for Merck, said early supporters of continuous manufacturing “will be most likely to win the largest benefits by shaping the way we adopt this new technology.”

He predicted continuous manufacturing will be fully integrated into the pharmaceutical industry by 2030. "If the food industry can adopt continuous manufacturing systems in producing potato chips, so can the pharmaceutical industry.”

Meyer based some of his projections on how much time the industry took to adopt hot melt extrusion, a technique used to process formulations containing polymers into sustained-release products. The number of hot melt extrusion patents issued for pharmaceutical applications grew from 13 in 1995 to 25 in 2005.

“We have seen a couple of approvals and the adoption curve is showing … by 2020 most of the industry will be invested and by 2025 the ICH countries will be accepting of continuous manufacturing and by 2030 roughly 30 years after we started it should be globally accepted,” Meyer said.

From the editors of the Gold Sheet.

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